In Mice and Men, a Shared Gene of Diabetes

12.09.14 - By using novel analysis tools, researchers from EPFL and ETH Zürich identified a gene in mice involved in the development of type 2 diabetes. A subsequent study in partnership with the CHUV revealed that the same gene is also involved in type 2 diabetes in humans, hinting at possible new approaches to research and treatment.

A joint study by EPFL, ETHZ and the CHUV has identified a pathological process that takes place in both mice and humans and causes one of the most common diseases that people face in the industrialized world: type 2 diabetes.

This work was conducted in Johan Auwerx’s (EPFL) and Ruedi Aebersold’s (ETHZ) laboratories, and succeeded thanks to the combination of each team’s strengths. The relevance of their discovery, published today in Cell, results from their joint effort.

In Lausanne, the researchers at EPFL and CHUV carried out a detailed study of the genome (the genetic make-up of an organism) and the phenome (the set of all observable phenotypes, or clinical traits) of a family of 183 mice. "By comparing the metabolism of twins subjected to different life conditions and different diets, it is possible to exactly assess the influence of the environment on the expression of certain genes and the way this affects clinical features and the risk for developing diseases", explained Auwerx, Director of the Laboratory of Integrative Systems Physiology (LISP) at EPFL.

Up to this moment, the combination of the genotypic and phenotypic information had already proved to be enlightening. In this instance, researchers added a new analytical layer obtained through new spectrometry technology developed at ETHZ, making it possible to quantify the presence of hundreds of proteins from a single sample and establish what experts call each individual’s proteome, or set of expressed proteins.

By combining each mouse’s genome, phenome, proteome and metabolome (the set of other chemicals found in a lab sample), the scientists were able to identify a particular gene located on chromosome 2 of the mice whose presence plays an important role in the development of type 2 diabetes.

"The mice with a diet high in fat are more or less likely to develop diabetes depending on whether this gene is active or not", said Evan Williams, a LISP PhD student and the Cell article’s co-first author. "By combining our various layers of information, we were able to establish exactly the process that leads from the presence of this gene to an increased risk of diabetes."

Another interesting fact is that diabetic mice have low urinary levels of a specific metabolite called 2-aminoadipate. Its concentration varies significantly depending on the presence of the identified gene, but not in relation to the rodents’ body fat. For researchers, this proves that it is indeed the gene, and not the diet, that regulates the expression of this protein.

"The strength of this correlation prompted us to ask ourselves whether it would also occur in the case of humans," said Williams. To find out, the researchers relied on the work of the Lausanne cohort (CoLaus) study, led by the CHUV, which recently published the results of tests from nearly 1,000 individuals. The facts were clear: in patients with type 2 diabetes, the rate of 2-aminoadipase was lower than in the rest, just like in mice

"Thanks to this innovative approach that connects several layers of information, we were able to identify a urinary marker that can easily detect the presence of a case of diabetes," said Johan Auwerx.

Other approaches like this will certainly help to develop new diagnostic tools applicable to other diseases. "It is very exciting to see that we can now translate research results from one species to another. To me, a new age for biology, and soon medicine, has just begun," Auwerx concluded.